The mission of the Cancer Mechanisms Program (CM) is to foster interdisciplinary collaborations and accelerate progress along the translational continuum between gene discovery and genotype-informed molecular treatments. CM organizes cancer-focused basic science on the Dartmouth Medical School, Dartmouth College, and Dartmouth-Hitchcock Medical Center campuses. CM investigators have common interests in dissecting the normal functions of oncogenes and tumor suppressor genes; regulators of cell cycle and apoptosis; regulators of angiogenesis and metastasis; and stem cells and blood formation. The CM Program adds value by channeling efforts toward three translational aims: molecular disease classification; drug target and lead compound identification; and understanding the complex interactions of small molecules and genotypes in carcinogenesis and treatment. By promoting collaborations among basic and clinical scientists from 10 departments, the 25-member Program has created advances that no single investigator could have made. CM investigators conduct research projects with a current annual total cost funding of $12.9 million ($2.9 million from NCI). Program members published more than 150 papers during the renewal period, of which 15% derived from intra-programmatic and 44% from inter-programmatic collaborations. CM has also assumed a leadership role in establishing and participating in comprehensive breast, lung, gastro-intestinal and neuro-oncology programs, thus uniting basic scientists with population scientists and clinicians to promote bidirectional translational research. CM scientists also organized regional and national meetings in hematological malignancies, lung cancer, and stem cells, out of which productive collaborations were formed. Going forward, CM will exploit advances such as a new mouse model for lung cancer to evaluate inhibitors of carcinogenesis, new targeted lead compounds against leukemogenic fusion proteins, and a newly discovered natural product that protects against chemotherapy-induced neurodegeneration, thereby translating CM discoveries to reduce cancer incidence, cancer death, and the pain and suffering associated with cancer treatment.